The Heart and Estrogen/progestin Replacement Study (HERS) and several other clinical studies and clinical trials have observed a transient increase in risk for coronary heart disease (CHD) events after initiation of hormone replacement therapy (HRT). Some evidence suggests that this adverse effect of HRT may be limited to a subgroup of women who are uniquely at risk for a thrombotic complication of estrogen therapy. There are several well-described polymorphisms in genes whose products regulate coagulation or fibrinolysis that could augment thrombotic risk in the setting of estrogen therapy. These polymorphisms include Factor V Leiden, prothrombin 20210A, Factor VII R353Q. plasminogen activator inhibitor-1 (PAI-1) 4G/5G, fibrinogen B-beta-455A, and platelet GP IIIa P1-A1.A2. We propose a nested case-control study among HERS women with CHD (n = 361) or venous thrombotic events (VTEs) (n = 95) and two clinic-matched controls to assess the relation between the above listed polymorphisms, HRT, and risk for CHD or VTEs. We will estimate the absolute and relative risk of HRT among women with and without the six candidate thrombosis gene polymorphisms and test for evidence of a genotype * HRT interaction. In secondary analyses, we will focus on events that occurred in the first year, evaluate the effect of triglycerides on risk associated with the Factor VII and PAI-1 polymorphisms, and explore the impact of combinations of polymorphisms on risk. DNA for this project will be acquired from centrally stored Pap smears that were collected during the trial. If this project reveals a high-risk subgroup based on thrombosis gene polymorphisms, women could be screened for this condition and cautioned not to use HRT. Conversely, low-risk women might be able to use HRT more safely in pursuit of various health benefits, including a possible reduction in CHD risk. Thus, this project may lead to more effective strategies to prevent CHD in women, enhance the safety of HRT, and add to the expanding body of knowledge concerning drug/gene interactions as they relate to treatment and prevention of disease.